A convenient synthetic route to (Sp)-methylphosphine borane derivatives via an asymmetric lithiation/trapping-reductive elimination strategy

Full text of DOI:10.1021/jo001537y

1514
J . Org. Chem. 2001, 66, 1514-1516
In all cases, stereochemical comparisons were made to
A Con ven ien t Syn th etic Rou te to
authentic racemates by chiral HPLC using a CHIRAL-
PAK AD column. A collection of representitive results
obtained via this sequence appears in Table 1.
In conclusion, we have shown that representitive
secondary phosphine boranes of high enantiopurity can
be readily prepared by an efficient asymmetric lithiation/
trapping-reductive elimination procedure. The subse-
quent utilization of new P-chirogenic ligands available
from these precursors, including those derived from 5a -
d , will be described in future accounts from these
laboratories.
(Sp )-Meth ylp h osp h in e Bor a n e Der iva tives
via a n Asym m etr ic Lith ia tion /
Tr a p p in g-Red u ctive Elim in a tion Str a tegy
Bradley Wolfe and Tom Livinghouse*
Department of Chemistry and Biochemistry, Montana State
University, Bozeman, Montana 59717
livinghouse@chemistry.montana.edu
Received October 30, 2000
Exp er im en ta l Section
Enantioenriched P-chiral secondary phosphine boranes
are extremely useful precursors for the synthesis of
P-chirogenic ligands for asymmetric catalysis.1 The most
common route used for the preparation of these com-
pounds involves the synthesis and resolution of diaster-
eomeric derivatives followed by reductive cleavage and
protonation.2 During the course of our studies on new
methods for the synthesis of enantiopure P-chiral phos-
phines,3 we required an alternative procedure for prepar-
ing the corresponding secondary phosphine boranes. In
this paper, we describe an efficient route to these
compounds in enantiopure form by asymmetric lithiation/
trapping-reductive elimination (Scheme 1).
Gen er a l Meth od s. All experiments were carried out under
an argon atmosphere in oven-dried glassware. Tetrahydrofuran
(THF) and diethyl ether (Et2O) were distilled from sodium
benzophenone ketyl. All other reagents were either prepared
according to published procedures or were available from com-
mercial sources and used without further purification. Column
flash chromatography was performed on Merck silica gel 60
(230-400 mesh) and Aldrich neutral alumina (∼150 mesh).
Chiral HPLC was performed using a CHIRALPAK AD [250 ×
4.6 mm (L × i.d.)] HPLC column (Daicel Chemical Industries).
(SP )-2-(Met h ylp h en ylp h osp h in ob or a n e)-1,1-d ip h en yl-
eth yl 2,2-Dim eth ylp r op ion a te (2a ).
The achiral dimethylphosphine borane precursors 1a-d
used in this study were typically prepared by the method
of Muci and Evans4 from chlorodimethylphosphine bo-
rane and the corresponding Grignard reagent. Asym-
metric lithiation of dimethylphosphine boranes 1a -d in
the presence of s-BuLi (-)-sparteine complex (Et2O, -78
°C)4 followed by sequential trapping of the resultant
organolithium derivatives with benzophenone and final
alkoxide acylation with trimethylacetyl chloride fur-
nished the enantioenriched adducts 2 in very good yields
on a preparative scale. Significantly, these highly crystal-
line compounds could usually be brought to >99% optical
purity by recrystallization from the appropriate solvent
system.5 In addition, simple reduction of these adducts
in the presence of lithium naphthalenide in THF or Li/
NH3-THF at -78 °C followed by protonation (MeOH)
gave the corresponding secondary phosphine boranes
3a -d with enantiopurities exceeding 99%. The optical
purities of 3a -d were determined by prior conversion to
appropriate tertiary phosphine boranes by alkylation of
the corresponding lithium derivatives with 2-(chloro-
methyl)benzothiophene to give the chiral P/S ligand
precursors 4a -d or benzyl bromide (for 3b)6 (Scheme 2).
To a cooled (-78 °C) solution of (-)-sparteine (2.6 mL, 11 mmol,
1.1 equiv) in ether (40 mL) was added s-butyllithium (9.2 mL,
11 mmol, 1.2 M in cyclohexane, 1.1 equiv) slowly via syringe.
The reaction mixture was allowed to stir for 10 min, and a
solution of dimethylphenylphosphinoborane (1.5 g, 10 mmol) in
ether (40 mL) was added dropwise via cannula. The reaction
mixture was allowed to stir at -78 °C for 3 h, and a solution of
benzophenone (2.0 g, 11 mmol, 1.1 equiv) in THF (10 mL) was
then added dropwise via cannula. The solution was stirred for
an additional 2 h at -78 °C and then warmed to 0 °C for 8 h. At
0 °C, trimethylacetyl chloride (1.8 mL, 15 mmol, 1.5 equiv) was
added, and the solution was allowed to stir as the ice bath
warmed to room temperature over 10 h. The solvent was then
removed in vacuo, and the thick heterogeneous oil was taken
up in dichloromethane (50 mL). To the mixture was added 5%
aqueous sulfuric acid (20 mL) in one portion, and the aqueous
phase was extracted with dichloromethane (3 × 20 mL). The
combined organic phases were washed with saturated sodium
bicarbonate (20 mL) and brine (20 mL), dried (MgSO4), filtered
(silica gel), and concentrated in vacuo. The resulting crude
colorless solid was purified by slow vapor recrystallization from
dichloromethane with pentane yielding (2.9 g, 6.9 mmol, 69%)
of (SP)-2-(methylphenylphosphinoborane)-1,1-diphenylethyl 2,2-
dimethylpropionate (2a ) as a colorless solid: mp 160.5-161.3 °C
(dichloromethane/pentane); [R]28D +18° (c ) 4.96, solvent THF);
(1) Yamanoi, T.; Imamoto, T. J . Org. Chem. 1999, 64, 2988-2989
and references therein.
(2) Miura, T.; Yamada, H.; Kikuchi, S.-i,; Imamoto, T. J . Org. Chem.
2000, 65, 1877-1880 and references therein.
(3) (a) Al-Masum, M.; Kumaraswamy, G.; Livinghouse, T. J . Org
Chem. 2000, 65, 4776-4778. (b) Al-Masum, M.; Livinghouse, T.
Tetrahedron Lett. 1999, 40, 7731-7734. (c) Wolfe, B.; Livinghouse, T.
J . Am. Chem. Soc. 1998, 120, 5116-5117.
(4) Muci, A. R.; Campos, K. R.; Evans, D. A. J . Am. Chem. Soc. 1995,
117, 9075-9076.
(5) In general, recrystallization to near optical purity could most
readily be achieved by solvent diffusion in a closed system.
(6) In the case of 3b, separation of the isomers 4b in an authentic
racemic mixture by chiral HPLC was not achieved. For this reason,
optical purity was established for the corresponding P-benzyl derivative
(6, see the Supporting Information).
IR (KBr) 3062, 2974, 2396 (BH), 1731 (CdO), 1151 (CO) cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.54-7.47 (m, 2H, Ar-H), 7.40-
7.06 (m, 13H, Ar-H), 3.74 (dd, J ) 14.7 Hz, J P-H ) 9.9 Hz, 1H,
PC(H)HC), 3.57 (dd, J ) 14.7 Hz, J P-H ) 11.7 Hz, 1H, PCH(H)C),
1.21 (s, 9H, C(CH3)3), 1.08 (d, J P-H ) 9.9 Hz, PCH3), 0.76 (very
broad s, 3H, BH3); 13C NMR (CDCl3, 75 MHz) δ 176.7 (s, -CO2-)
144.4 (d, J P-C ) 5.1 Hz, ArC), 144.1 (d, J P-C ) 6.0 Hz, ArC),
131.1 (d, J P-C ) 9.1 Hz, ArC), 130.7 (d, J P-C ) 1.3 Hz, ArC),
130.5 (d, J P-C ) 27.2 Hz, ArC), 128.5 (d, J P-C ) 9.9 Hz, ArC),
128.2 (s, ArC), 128.0 (s, ArC), 127.5 (s, ArC), 127.4 (s, ArC), 126.2
(s, ArC), 126.1 (s, ArC), 83.4 (s, RPh2CO-), 39.1 (s, CC(CH3)3),
36.5 (d, J P-C ) 32.3 Hz, PCH2C), 127.1 (s, C(CH3)3), 11.4 (d, J P-C
10.1021/jo001537y CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/31/2001

Notes
J . Org. Chem., Vol. 66, No. 4, 2001 1515
Sch em e 1
Ta ble 1. P r ep a r a tion of En a n tioen r ich ed Secon d a r y P h osp h in e Bor a n esa
% ee before
% yield
% yield
Ar
recrystallization
(>99% ee)
(>99% ee)
C6H5
75
>99
87
69b
70c
76b
46b
93
94
93
99
2-(i-Pr)C6H4
2-(Me)C6H4
2-(MeO)C6H4
83
a
b
Absolute stereochemistry of 3a -d was assigned (S) by analogy.4 Percent ee determined by chiral HPLC using a CHIRALPAK AD
column. c Percent ee determined by anology to the corresponding alcohol 5b (see the Supporting Information).
equiv) in THF (5.0 mL) was added dropwise via cannula to a
cooled (-78 °C) solution of lithium naphthalenide (5.0 mL, 2.5
mmol, 0.5 M, 5.0 equiv). The solution was allowed to stir for 10
min, and a mixture of THF, MeOH, and AcOH (8:1:1) (0.5 mL)
was added very slowly. To the resulting solution were added
saturated ammonium chloride (2 mL), water (2 mL), and ether
(5 mL). The aqueous phase was extracted with ether (3 × 10
mL). The combined organic phases were washed with brine and
then dried (MgSO4), filtered, and concentrated in vacuo. The
amorphous crude solid was purified by flash column chroma-
tography on silica gel (5% ethyl acetate/ hexanes for elution)
yielding (SP)-methylphenylphosphine-borane (3a ) (85 mg, 0.46
Sch em e 2
mmol, 93%) as a colorless oil: [R]24 -8.3° (c ) 1.20, sol. THF);
D
IR (film, NaCl) 3057, 2394 (BH), 1064 (broad), 995 (sharp), 930
1
(broad), 738 cm-1; H NMR (CDCl3, 300 MHz) δ 7.73-7.65 (m,
2H, Ar-H), 7.54-7.42 (m, 3H, Ar-H), 5.59 (d sep, J P-H ) 370.8
Hz, J ) 6.3 Hz, 1H, PH), 1.61 (dd, J P-H ) 11.1 Hz, J P-H ) 6.3
Hz, 3H, PCH3), 0.80 (q, J B-H ) 99.0 Hz, 3H, PBH3); 13C NMR
(CDCl3, 75 Hz) δ 132.0 (d, J P-C ) 9.2 Hz, PhC), 131.4 (d, J P-C
2.3 Hz, PhC), 128.8 (d, J P-C ) 10.3 Hz, PhC), 126.1 (d, J P-C
)
)
) 39.2 Hz, PCH3); 31P NMR (CDCl3, 121 MHz) δ 5.4 (apparent
broad d, J B-P ) 59.9 Hz); TLC Rf 0.14 (10% ethyl acetate/
hexanes); LRMS m/z (EI) 404 (M+ - BH3, 5.7%) 57, 77, 89, 109,
124, 140, 165, 180 (100%), 200, 301; exact mass calcd for
C26H29O2P (M+ - BH3) requires m/z 404.1917 found m/z 404.1905.
Separation of the enantiomers of the recrystallized product with
chiral HPLC (CHIRALPAK AD, 10% i-PrOH/ hexanes, 1.0 mL/
min, tR ) 4.78 (major), 6.42 min) indicated an ee of >99%.
(SP )-Meth ylp h en ylp h osp h in obor a n e (3a ).
56.5 Hz, PhC), 8.1 (d, J P-C ) 38.4 Hz, PCH3); 31P NMR (CDCl3,
121 MHz) δ -16.0 (apparent q, J B-P ) 52.3 Hz); TLC Rf 0.22
(10% ethyl acetate/hexanes).
(SP )-Ben zo[b]th iop h en e-2-ylm eth ylp h en ylm eth ylp h os-
p h in obor a n e (4a ).
n-Butyllithium (280 µL, 0.47 mmol, 1.7 M in hexanes, 1.1 equiv)
was added dropwise to a cooled (-78 °C) solution of (SP)-
methylphenylphosphinoborane (3a ) (59 mg, 0.43 mmol), HMPA
(146 µL, 0.84 mmol, 2.0 equiv), and THF (1.0 mL). The solution
A solution of (SP)-2-(methylphenylphosphinoborane)-1,1-diphen-
ylethyl 2,2-dimethylpropionate (2a ) (230 mg, 0.50 mmol, 1.0

1516 J . Org. Chem., Vol. 66, No. 4, 2001
Notes
was stirred for 10 min, and a solution of 2-chloromethylbenzo-
[b]thiophene (86 mg, 0.47 mmol, 1.1 equiv) in THF (1.0 mL) was
added dropwise slowly. The solution was allowed to stir for 10
h at -78 °C, and water (3.0 mL) was added. The aqueous phase
was extracted with ether (3 × 2 mL), and the combined organic
phases were washed with brine (3 mL), dried (MgSO4), filtered,
and concentrated in vacuo. The crude light yellow solid was
purified by flash column chromatography (gradient elution with
20-50% dichloromethane/ hexanes) yielding (SP)-benzo[b]-
thiophene-2-ylmethylphenylmethylphosphinoborane (4a ) (110
mg, 0.39 mmol, 94%) as a colorless solid: mp 136.4-138.3 °C
(dichloromethane/hexanes); [R]28D -63° (c ) 1.00, solvent THF);
IR (KBr) 3054, 2402 (BH), 2377 (BH), 2347 (BH), 1432 (sharp),-
ArC), 123.0 (s, ArC), 121.8 (s, ArC), 30.9 (d, J P-C ) 31.7 Hz,
PCH2Ar), 9.0 (d, J P-C ) 38.2 Hz, PCH3); 31P NMR (CDCl3, 121
MHz) δ 11.5 (apparent broad d, J B-P ) 68.0 Hz); TLC Rf 0.15
(10% ethyl acetate/hexanes); LRMS m/z (EI) 270 (M+ - BH3,
42%) 77, 103, 121, 136, 147 (100%), 240, 270; exact mass calcd
for C16H15PS (M+ - BH3) requires m/z 270.0632, found m/z
270.0637. Separation of the enantiomers by chiral HPLC
(CHIRALPAK AD, 10% i-PrOH/hexanes, 1.0 mL/ min, tR) 8.79
(major), 10.14 (min) demonstrated the ee to be >99%.
Ack n ow led gm en t. Generous financial support for
this research by a grant from the National Science
Foundation is gratefully acknowledged.
1066 (sharp), 738 (broad) cm-1 1H NMR (CDCl3, 300 MHz) δ
;
7.73-7.59 (m, 4H, Ar-H), 7.51 (m, 1H, Ar-H), 7.45-7.39 (m, 2H,
Ar-H), 7.32-7.23 (m, 2H, Ar-H), 6.86 (d, J ) 3.0 Hz, 1H, Ar-H),
3.49 (dd, J ) 25.2, 15.6 Hz, 2H, PCH2Ar), 1.61 (d, J P-H ) 9.9
Hz, 3H, PCH3), 0.85 (very broad q, J B-H ) 109.8 Hz, 3H, BH3);
13C NMR (CDCl3, 75 MHz) δ 139.5 (d, J P-C ) 2.6 Hz, ArC), 139.4
(s, ArC), 134.4 (d, J P-C ) 8.6 Hz, ArC), 131.6 (d, J P-C ) 9.3 Hz,
ArC), 131.5 (s, ArC), 128.6 (d, J P-C ) 9.8 Hz, ArC), 128.3 (d,
J P-C ) 52.8 Hz, ArC), 124.2 (s, ArC), 124.0 (s, ArC), 123.9 (s,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and listings of H, 13C, and 31P NMR, IR, and HRMS
or elemental composition data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O001537Y